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International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

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Review

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Glycerol monooleate liquid crystalline phases used in drug delivery systems

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S. Milak, A. Zimmer *

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University of Graz, Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, NAWI Graz, Universitätplatz 1, 8010 Graz, Austria

A R T I C L E I N F O

A B S T R A C T

Article history: Received 17 July 2014 Received in revised form 20 November 2014 Accepted 29 November 2014 Available online xxx

During the last few decades, both scientific and applied research communities have shown increased attention to self-assembled lyotropic liquid crystalline phases of polar lipids, due to their remarkable structural complexity and usefulness in diverse applications. Amphiphilic properties of polar lipids in relation to water are the driving force for self-assemblies following an extraordinary polymorphism. This polymorphism is an interesting phenomenon in which lipids combine short-range disorder and long-range order. The most widely investigated liquid crystalline phases are the lamellar, the cubic and the hexagonal. Such phases have high solubilization capacity for hydrophilic, lipophilic and amphiphilic guest molecules and the ability to protect molecules against hydrolysis or oxidation. So, they can be used as an interesting drug delivery matrix for drugs, amino acids, peptides, proteins and vitamins in various food, pharmaceutical and biotechnical applications. This review presents recent progress in glycerol monooleate liquid crystalline phases used as drug delivery vehicles. ã 2014 Published by Elsevier B.V.

Keywords: Glycerol monooleate Liquid crystalline phase Cubic phase Hexagonal phase Drug delivery

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Glycerol monooleate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The structure of liquid crystalline phases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The reversed cubic liquid crystalline phase . . . . . . . . . . . . . . . . . . . . . 3.1. The reversed hexagonal liquid crystalline phase . . . . . . . . . . . . . . . . . 3.2. The lamellar liquid crystalline phase (La) . . . . . . . . . . . . . . . . . . . . . . . 3.3. Intermediate phases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Phase diagram of glycerol monooleate/water . . . . . . . . . . . . . . . . . . . . . . . . . . Introduction of guest molecules in the liquid crystalline phases . . . . . . . . . . Introduction of guest molecules in the reversed cubic phase . . . . . . . 5.1. 5.2. Introduction of guest molecules in the reversed hexagonal phase . . . Introduction of guest molecules in the reversed micellar cubic phase 5.3. Introduction of guest molecules in the bicontinuous sponge phase . . 5.4. Characterization of liquid crystalline phases . . . . . . . . . . . . . . . . . . . . . . . . . . Polarized light microscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. 6.2. X-ray diffraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential scanning calorimetry (DSC) . . . . . . . . . . . . . . . . . . . . . . . . 6.3. 6.4. Rheology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: SAXS, small-angle X-ray scattering; DSC, differential scanning calorimetry; NMR, nuclear magnetic resonance; FTIR, Fourier transform infrared spectroscopy; MTT, (3-(4,5-dimethylthiazol-2-yl)-2,5-dyphenyl tetrazolium bromide; TGA, thermogravimetry analysis; PEG, polyethylene glycol; M, molar; mM, millimolar; Mr, molecular mass. * Corresponding author at: University of Graz, Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, NAWI Graz, Universitätsplatz 1, 8010 Graz, member of: BioTechMed Graz, Austria. Tel.: +43 316 380 8881; fax: +43 316 389 9100. E-mail address: [email protected] (A. Zimmer). http://dx.doi.org/10.1016/j.ijpharm.2014.11.072 0378-5173/ ã 2014 Published by Elsevier B.V.

Please cite this article in press as: Milak, S., Zimmer, A., Glycerol monooleate liquid crystalline phases used in drug delivery systems. Int J Pharmaceut (2014), http://dx.doi.org/10.1016/j.ijpharm.2014.11.072

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6.5. Low frequency dielectric spectroscopy . . . . . Spectroscopic methods (NMR, IR- and Raman 6.6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Liquid crystalline phases are frequently encountered in everyday life. For example, the cell membranes in the body are the result of the lyotropic liquid crystalline phase that is generated from the Q2 dissolution of phospholipids in water (Collings and Hird, 1997; Seddon and Templer, 1995). Probably, microsomes’ membranes, mitochondria and tight junctions between cells are formed from non-lamellar liquid crystalline structures. Etiolated chloroplasts, which consists of six-fold or four-fold interconnected tubular membrane structures, are strikingly similar to the structure elements of the inverse bicontinuous cubic phases. The structures of certain membranous organelles in cells, for example in endoplasmic reticulum, bear a quite striking similarity to the sponge phase. It has been assumed that liquid crystalline phases, possibly including cubic phases, play a role in the process of fat digestion in vivo (Collings and Hird, 1997; Lynch and Spicer, 2005; Seddon and Templer, 1995). During this process, triglyceride is hydrolyzed first to diacylglycerol plus fatty acid, then to monoacylglycerol plus two fatty acid molecules. Research on phase equilibria of lipid mixtures similar to those found in the intestine showed that liquid crystalline phases, as well as an inverse micellar solution, were formed and it was suggested that the latter phase may coexist with mixed micelles in the human intestine. These phases have an important property that all reactants and products, whether polar, non-polar or amphiphilic can diffuse freely across the structure. Accordingly, life itself critically depends upon liquid crystalline phases. Liquid crystals show properties between those of conventional liquid and solid crystals (Seddon and Templer, 1995). For instance, a liquid crystal may flow like a liquid but have the molecules in the liquid arranged and oriented in a crystal-like way. The type of molecular structure that generates liquid crystalline phases is amphiphilic (Collings and Hird, 1997; Seddon and Templer, 1995). The amphiphilicity implies the dualistic properties of the molecules in relation to water, with flexible hydrocarbon chains avoiding water contact and a polar head group that tends to orient towards water. Amphiphilic molecules form aggregates through a self-assembly process that is driven by the “hydrophobic effect” when they are mixed with a solvent (usually water). The aggregates formed by amphiphilic molecules are characterized by structures in which the hydrophilic head-groups shield the hydrophobic chains from contact with water. For most lyotropic systems aggregation occurs only when the concentration of the amphiphile exceeds a CMC (critical micelle concentration) or the CAC (critical aggregation concentration). Above the CMC the selfassembled amphiphile aggregates exist as independent entities, in equilibrium with monomeric amphiphiles in solution, and with no long ranged orientational or positional (translational) order. These dispersions are micellar solutions (its constituent aggregates are micelles, generating isotropic phases). The lyotropic liquid crystalline phases are formed as the concentration of amphiphile in water is increased beyond the point where the micellar aggregates are forced to be disposed regularly in space. For amphiphiles that consist of a single hydrocarbon chain the concentration at which the first liquid crystalline phases are formed is typically in the range 25–30 w/w%. In the same way, polar lipids, as amphiphilic molecules, have a remarkable ability to self-assembly in water to form different

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structures. In the solid state, the general structure of lipids is a stack of planar molecular bilayers. The hydrocarbon chains are close-packed in these bilayers, and the polar heads form the outer surfaces. The hydrogen-bond system in the sheets formed by the polar head groups is strong compared to the weak van der Waals interaction between the hydrocarbon chains (Collings and Hird, 1997; Larsson, 1989, 2000; Seddon and Templer, 1995). During the melting of this structure, first the hydrocarbon chains become disordered into a liquid-like structure, with the overlying gross structure remaining intact, then, at a higher temperature the complete melting occurs. In solids, planar zigzag conformations of the carbon–carbon bonds exist (all-trans), whereas in disordered states, occurring in liquid crystals and in melts, gauche conformations form dynamically along the chain. The combination of disorder on the atomic scale with the long-range order in layers is the characteristic property of liquid crystalline phases of lipids. Several review articles about lipid liquid crystalline phases have been published to give insights into their structure and the diversity of applications. The purpose of this review is to summarize the data about drug delivery systems based on glycerol monooleate liquid crystalline phases (Amar-Yuli et al., 2009; Caboi et al., 2001; Chernik, 1999; Drummond and Fong, 1999; Engström, 1990; Fong et al., 2012; Garti et al., 2012; Guo et al., 2010; Hitesh et al., 2011; Kaasgaard and Drummond, 2006; Kulkarni et al., 2011; Larsson, 2009; Leser et al., 2006; Sagalowicz et al., 2006a,b; Shah et al., 2001).

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2. Glycerol monooleate

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Glycerol monooleate is one of the most widely studied amphiphilic lipid used in the formation of various liquid crystalline drug formulations (Ganem-Quintanar et al., 2000). Glycerol monooleate (Fig. 1) is a glycerol fatty acid ester. It has a cis double bond at C9. From the molecular point of view, glycerol monooleate has the acyl chain which is by an ester bond attached to the glycerol backbone (Ganem-Quintanar et al., 2000; Kulkarni et al., 2011). The two remaining carbons of the glycerol moiety are free, giving polar characteristics to this part of the molecule. This hydrophilic part can form hydrogen bonds with water in an aqueous environment (the headgroup). The hydrocarbon chain (the tail) gives hydrophobic properties to glycerol monooleate. Glycerol monooleate is a lipophilic substance, HLB = 3–4, almost insoluble in an aqueous phase. Its solubility in water is ffi106 M and it forms micellar solution with water above its critical aggregation concentration, approx. 4  106 M (Barauskas et al., 2010).

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Fig. 1. Chemical structure of glycerol monooleate.

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Furthermore, glycerol monooleate is a nontoxic, biodegradable and biocompatible material, classified as GRAS (generally recognized as safe) and it is included in the FDA Inactive Ingredients Guide (Bode et al., 2013; Ganem-Quintanar et al., 2000; Matschke et al., 2002). One important aspect of the use of glycerol monooleate as a safe parenteral material is the necessity to confirm its biological tolerance. Although glycerol monooleate disappears after in vivo subcutaneous and intramuscular injection, principally by lipase activity, its nonirritant effect on the tissues has not been entirely confirmed. Glycerol monooleate has hemolytic properties and therefore it is not suitable for intravenous administration. Glycerol monooleate was first used in 1930 in the margarine production (Ganem-Quintanar et al., 2000). Today, it is used as a processing aid in the production and stabilization of emulsions and foams in bread, cakes, margarine, ice creams and chewing gums. Its major functions are absorption at interface or on solids, promotion of wetting phenomena, co-crystallization, complex formation (with proteins or starch components) and self-association. In the pharmaceutical area, glycerol monooleate was first used as an emulsifier and an absorption enhancer in combination with bile salts (Dash et al., 1999; Ganem-Quintanar et al., 2000; Herai et al., 2007). As an absorption enhancer, glycerol monooleate probably acts by causing a temporary and reversible disruption of the lamellar structure of the lipid bilayer in the stratum corneum and, in this way, increasing intercellular lipid fluidity. As a biocompatible encapsulating material, glycerol monooleate was first proposed in 1984. Since then many papers were released and new applications were proposed. Extremely helpful for all new applications was the significant advance in understanding the physico-chemical properties of glycerol monooleate.

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3. The structure of liquid crystalline phases

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Liquid crystalline phases, having long-ranged orientational order, are induced by the addition of a solvent (lyotropic liquid crystalline phases) or by temperature (thermotropic liquid crystalline phases) (Chernik, 1999; Larsson et al., 2006; Larsson, 2009). Three main classes of lyotropic liquid crystalline phase structures are: the lamellar, the hexagonal and the cubic phases, and their structures have been classified by X-ray diffraction techniques. The most widely used nomenclature for lyotropic phases (Collings and Hird, 1997; Hyde, 2001; Lynch and Spicer, 2005; Seddon and Templer, 1995) is that proposed by Luzzati and this is denoted by a capital letter, e.g., L for lamellar, H for hexagonal, Q for cubic. Subscripts I and II are used to denote normal (oil in water) or reversed (water in oil) topology phases. A Greek subscript is used to denote the chain conformation: c for crystalline, b for ordered gel-like, a for liquid-like, ab for coexisting gel- and liquid-like regions.

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3.1. The reversed cubic liquid crystalline phase

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The name cubic comes from the fact that its X-ray diffraction pattern shows cubic symmetry (Larsson et al., 2006; Seddon and Templer, 1995). The cubic liquid crystalline phases exhibit the most complex spatial organization of all known liquid crystalline phases. There are two distinct families of cubic phases: bicontinuous (based on underlying periodic minimal surfaces) and micellar (based on complex packings of discrete micellar aggregates). Both types may be normal (oil-in-water) or inverse (water-in-oil). The general structure principle of the bilayer curvature in bicontinuous cubic phases could be described by the infinite periodic minimal surface (IPMS), whereas its dynamic structure could be better described by the nodal surface. The bilayer in a cubic phase is far from being static, as a minimal surface (Larsson, 2000).

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In the bicontinuous cubic phase, a minimal surface has an average curvature equal to zero everywhere (Seddon and Templer, 1995), which means that the pressure gradient is equal to zero. This unique curvature of the bilayer in the cubic phase is associated with the curvature elastic energy which determines the stability of the cubic phase as a function of composition. Spontaneous formation and thermodynamic stability of a cubic phase, consisting of bicontinuous bilayers arranged in geometries of periodic minimal surfaces found in many lipid/water systems, are due to a competition between the two free energy terms: the curvature energy of each monolayer versus the stretching energy of the lipid chains. To date three cubic bicontinuous phases have been identified (Collings and Hird, 1997; Larsson et al., 2006; Lynch and Spicer, 2005; Seddon and Templer, 1995), based on these three surfaces: the P (Im3m), the D (diamond, Pn3m) and most frequently, the G (gyroid, Ia3d) bicontinuous liquid crystal phases (Fig. 2). Such surfaces describe the mid-surface of the amphiphilic bilayer (Hyde, 2001). Probably there are many other examples of cubic phases, that have not yet definitely been identified, so more cubic phases remain to be discovered. In summary, Garti et al. (2012), described the seven cubic structures which were discovered so far. Glycerol monooleate at low water content forms the bicontinuous cubic phase with space group Ia3d (proposed to be a G-surface) and then, at higher water content, the Pn3m phase is obtained (Larsson et al., 2006; Lynch and Spicer, 2005; Seddon and Templer, 1995). In terms of minimal surfaces, the inverse bicontinuous cubic phases Ia3d, Pn3m and Im3m are formed by dripping a continuous lipid bilayer onto the gyroid, F- and P-minimal surfaces, respectively. These three surfaces constitute a family of infinite periodic minimal surfaces which are related to each other by the Bonnet transformation. This means that one surface can be transformed into either of the others by bending, which leaves the Gaussian curvature at all points unchanged, and preserves all angles, distances and areas on the surface. These transitions between bicontinuous liquid crystalline phases are

Fig. 2. Schematic representations of the various crystals, liquid crystal and fluid phases identified in the temperature–composition phase diagram of glycerol monooleate. Adopted from (Qiu and Caffrey, 2000).

Please cite this article in press as: Milak, S., Zimmer, A., Glycerol monooleate liquid crystalline phases used in drug delivery systems. Int J Pharmaceut (2014), http://dx.doi.org/10.1016/j.ijpharm.2014.11.072

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common, often requiring only small changes in composition (or temperature). The gyroid (G), Ia3d structure consists of two interwoven yet unconnected chiral networks of water/lipid cylinders, connected coplanarly three by three and separated by the G-minimal surface. As in the other minimal surface structures, the two continuous water compartments, separated by one continuous lipid bilayer, are congruent and have no contact with one another. In the G-surface type of bilayer structure, the water channels between the structure units follow a helical network, with three connections/openings between each unit. The structure of diamond (D), Pn3m consists of two interwoven tetrahedral networks of water channels arranged on a doublediamond lattice, separated by the F-minimal surface. The third bicontinuous cubic phase, Im3m has orthogonal network of water channels connected six-by-six, and separated by the P-minimal surface. With six connectivities, the P-surface structure in the glycerol monooleate system is formed only when the water compartments are expanded by an amphiphile, whereas successive reduction of the aqueous volume forms first the Dsurface with four connectivities, and finally the G-surface structure with three connectivities. The first well-established example of a cubic phase composed of a packing of discrete inverse micelles is the phase Fd3m. The Fd3m structure has two types of aggregates, both are quasispherical but of different sizes. There are 8 of the larger and 16 of the smaller inverse micelles per unit cell. Cubic liquid crystalline phases are extremely viscous (sometimes termed “ringing gels” in the older literature). They are even more viscous than the hexagonal phases. The high viscosity is a result of the lack of shear planes within the structure that would allow a sliding movement. The arrangement of the molecular aggregates in cubic phases (cubic symmetries) means that they are optically isotropic and do not display optical textures (Collings and Hird, 1997; Lynch and Spicer, 2005). As with other liquid crystalline systems, e.g., reversed hexagonal phase and reversed micellar cubic phase, the cubic phase under full hydration conditions is physically stable upon contact with excess water (de Campo et al., 2004). Except glycerol monooleate, this was shown on the example of other lipids, such as monolinolein (de Campo et al., 2004) and monoeladin (having the same molecular weight as glycerol monooleate, but different molecular shape) (Yaghmur et al., 2008, 2012a).

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3.2. The reversed hexagonal liquid crystalline phase

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The reversed hexagonal liquid crystalline phase has a molecular aggregate ordering which corresponds to a hexagonal arrangements (Collings and Hird, 1997; Hyde, 2001). It consists of a dense packing of cylindrical micelles, arranged on a 2D hexagonal lattice. Water is contained within the cylindrical reversed micelles which have a diameter of 1–2 nm. The remaining space is occupied by the non-polar chains which overlap to leave the cylinders much closer together than in the normal hexagonal phase. Usually they contain 30–60% water by weight, and despite this high water content the phase is very viscous. This anisotropic phase is of intermediate viscosity to discrete micellar and bicontinuous cubic phases. By optical polarizing microscopy, it is identified by a characteristic “fan” textures, due to focal conic domains of columns.

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3.3. The lamellar liquid crystalline phase (La)

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The lamellar structure makes the basic building block of all biological membranes (Garti et al., 2012). Lamellar phase consists of planar lipid bilayers stacked in a one-dimensional lattice separated by layers of water (Collings and Hird, 1997; Hyde, 2001;

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Larsson et al., 2006; Seddon and Templer, 1995). This bilayer conformation is formed when layers of water interpenetrate polar heads groups. The bilayer thickness is 10–30% less than twice the length of an “all-trans” non-polar chain, and the water layer thickness is between 1 and 10 nm if the water content is between 10 and 50% in weight. Lamellar liquid crystalline phases are less viscous than the hexagonal liquid crystalline phases despite the fact that they contain less water. This is described by the parallel layers which slide over each other with relative ease during shear. The a subscript refers to the molten chains in this phase. Like all anisotropic phases, lamellar liquid crystalline phases exhibit distinct optical textures, when confined in thin slabs between crossed polarizers and viewed through an optical microscope. Typically, the texture is “streaky” or mosaic-like and resembles the marbling in freshly cut steak. Alternatively, lamellae can eradicate all edges by folding into vesicles – essentially spherical globules. These are typically multiwalled (liposomes), exhibiting characteristic “maltese cross” textures in the optical microscope.

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3.4. Intermediate phases

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A variety of other intermediate phases have been proposed in the scientific literature over the years such as novel arrays of meshes, sponges and hybrids (Hyde, 2001; Seddon and Templer, 1995). Certain surfactant systems form highly swollen lamellar phases, which may transform upon dilution to a sponge phase (L3) (Drummond and Fong, 1999; Engström et al., 1998; Kulkarni et al., 2011). This phase is essentially a disordered version of the bicontinuous cubic phases whose interface is highly flexible. Also, thermal excitations lead to the breakdown of the long range order of the channel network so that the interface is no longer arranged on a lattice. Sponge phases are characterized by flow of birefringence (giving anisotropic optical textures), yet they are isotropic at rest. They often form at high (water) dilution, usually in regions of the phase diagram intermediate to lamellar and bicontinuous cubic mesophases. Among many intermediate phases reported, more work needs to be done in order to sort out these phases.

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4. Phase diagram of glycerol monooleate/water

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A phase diagram presents the system behavior in thermodynamic equilibrium, when the system is in the lowest state of free energy (Chernik, 1999; Larsson, 2009; Larsson et al., 2006; Leser et al., 2006; Qiu and Caffrey, 2000). There is a “natural” sequence in which the various possible fluid phases occur, determined by the average mean curvature of the polar–nonpolar interface (Seddon and Templer, 1995). Water content and temperature present the primary variables for binary lipid/water systems. The phase diagram of glycerol monooleate/ water shows that at 37  C (pure monoolein melts at 36  C) and in the presence of a small amount of water, glycerol monooleate forms reversed micelles (L2), characterized by an oily texture (Fig. 3). Adding more water, a mucous like system is formed that corresponds to the lamellar phase. In general, there will be a tendency for the monolayer to curve, either towards the water region or towards the hydrocarbon chain region, depending on whether the interfacial tension is balanced primarily by the chain pressure or the headgroup pressure, respectively. By adding more water (20–40%), a large isotropic cubic liquid crystalline phase G (gyroid, Ia3d) is formed. At more than 40% of water, the cubic liquid crystalline phase D (diamond, Pn3m) exists which is in equilibrium with pure water. Glycerol monooleate is a unique lipid in exhibiting a wide region with cubic structures in the phase diagram, both in composition and in temperature (including the room temperature). At the temperature above 80  C the hexagonal phase appears, which exists in equilibrium with water as well.

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parameter, cpp (or critical packing parameter) (Engström, 1990; Engström and Engström, 1992; Hyde, 2001; Kaasgaard and Drummond, 2006). cpp ¼

Fig. 3. Temperature–composition phase diagram of the monoolein/water system (up to 50 wt% water). The phases are: Lc – crystal lamellar, La – lamellar, Ia3d – gyroid reversed bicontinuous cubic, Pn3m – primitive reversed bicontinuous cubic, HII – reversed hexagonal and FI – reverse micelles isotropic fluid phase. Adopted from (Qiu and Caffrey, 2000). 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370

A compilation of lipid phase diagrams has been published and databases of lipid transition temperatures and enthalpies are given by Caffrey et al. (1991). Qiu and Caffrey (2000), described the glycerol monooleate–water phase diagram at temperatures below 20  C, where there exists a complicated behavior involving metastable phases. Glycerol monooleate can be obtained in a highly pure form. However, in most studies in the literature, commercial monoglycerides are used, such as Dimodan U, Monomuls, Myverol. Commercial monoglycerides contain different monoglycerides, diglycerides and free fatty acids, with the dominant component – monooleate. The phase diagram of such a mixture behaves like that of a pure component. 5. Introduction of guest molecules in the liquid crystalline phases During the last few decades glycerol monooleate liquid crystalline bulk phases have been investigated as an interesting drug delivery matrix for both conventional and peptide/protein drugs (Table 1). This is connected with their high solubilization capacities for hydrophilic, lipophilic and amphiphilic guest molecules, abilities to protect molecules against hydrolysis or oxidation and to keep peptide/protein in their native conformation. All additives, more or less significantly, influence the phase behavior. After solubilization of a certain “critical” amount of additive, a phase transition is induced. Each additive affects the interfacial curvature of the lipid bilayer in a different way. Generally, lipophilic additives induce a transition from a reversed bicontinuous cubic to reversed hexagonal phase, i.e., the mean interfacial curvature becomes more negative. However, more hydrophilic additives induce the transition from the reversed bicontinuous cubic to the lamellar, i.e., the mean interfacial curvature changes towards zero. The changes in the molecular geometry are used to explain phase transitions as well as intercubic transformations, in lipid–water systems. The self-assembly of lipid molecules can be described by the use of a dimensionless packing parameter (Engström, 1990; Engström and Engström, 1992; Fong et al., 2012; Hyde, 2001; Kaasgaard and Drummond, 2006). The concept of the packing parameter is very useful for qualitative/ semiquantitative considerations. According to this concept, the shape of molecules is defined as the dimensionless packing

V al

371 372 373

(1)

where V: molecular volume; l: molecular length; a: effective (or Q3 hydrated) cross-sectional area of the polar head group. If an amphiphile is an aggregate and can be mimicked by a cylinder, then cpp = 1. The amphiphiles with cpp near 1 aggregate with a planar interface, as in a lamellar phase. If cpp is far from 1, then 2 cases are possible. For the amphiphilic molecules with a large polar head group area, cpp is less than 1 (al > V) and these molecules will aggregate to the normal type in water, such as micelles of spherical and cylindrical shape. If the polar head group area of the amphiphile molecule is small, the cpp is larger than 1 (al < V) and inverted micelles are formed.

375 374 376

5.1. Introduction of guest molecules in the reversed cubic phase

386

One of the first substances investigated in the glycerol monooleate cubic liquid crystalline phase was lysozyme (Ericsson et al., 1983). The same research group revealed that lysozyme was located in the water channel system. Lysozyme kept its native structure and increased the lattice dimensions. Investigating other proteins, such as a-lactalbumin, bovine serum albumin, myoglobin, pepsin to form the cubic phase, Ericsson et al. (1983), found out that high apparent net charge repulsion between the protein molecules favors the creation of the cubic glycerol monooleate– protein–water phase. Formation of the cubic phase is favored by an isoelectric point far from pH 7 in a salt-free solution (by high electrostatic repulsive forces). Liquid crystalline lipid–protein– water phases are formed only when there is a possibility for ionic interaction between lipid and protein molecules. In addition, the same research group also investigated the incorporation of different peptides and aminoacids: desmopressin, lysine, vasopressin, somatostatin and renin inhibitor into the cubic phase of glycerol monooleate/water (Ericsson et al., 1991). They found out that these peptides could be incorporated into the cubic phase up to 5–10% w/w. Above the certain concentrations of the water soluble oligopeptides, the phase transformation was noted from the cubic phase to the lamellar phase which was explained by electrostatic repulsion at the glycerol monooleate–water interface caused by the peptide. For desmopressin, they found that its diffusion coefficient in the cubic phase at 40  C, D = 0.24  1010 m2 s1, is about a factor 9 smaller than in water at 25  C, D = 2.25  1010 m2 s1. Engström (1990) and Engström and Engström (1992), investigated the glycerol monooleate/water system (cubic phase) with lidocaine HCl. In the example of lidocaine HCl, the cubic phase was transformed into the lamellar liquid crystalline phase. However, when the base form of lidocaine is added, transition of the cubic phase to reversed hexagonal liquid crystalline phase occurs. With the same amount of the salt and lidocaine base, the cubic phase persisted. Lidocaine in both forms and the interfacial curvature changes in the opposite direction in relation to the curvature of the cubic phase participate in the lipid aggregation. This was explained by the packing concept of amphiphilic molecules (cpp). Engström and Engström (1992), assumed that cpp for lidocaine HCl is less than 1.2 and for the base form is larger than 1.2. The cubic phase is preserved by cancelling the deviations of the cpp valued from 1.2 when the base and salt forms are mixed in roughly equal amounts. Wyatt (1992), incorporated drugs of different size (Mr) and solubility (vitamin E TPGS, hydroxychloroquine sulfate, diclofenac sodium, aspirin), into the cubic phase (glycerol monooleate, water

387

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377 378 379 380 381 382 383 384 385

388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432

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Table 1 Studies done incorporating different molecules in glycerol monooleate liquid crystalline phases. No. System investigated

Parameters studied

Characterization Techniques/analyses

Refs.

1

Glycerol monooleate/water/lysozyme

Ternary phase diagram, thermal stability of the protein structure in a cubic glycerol monooleate/ water phase

(Ericsson et al., 1983)

2

Glycerol monooleate and monoeladin/NaCl solution (0–5 M), at 20–120  C Glycerol monooleate/water/desmopressin, lysine vasopressin, somatostatoin, renin inhibitor (subcutaneous or intramuscular depot for extended peptide release) Glycerol monooleate/water/lidocaine, lidocaine HCl

Dynamics and mechanism of the various thermotropic phase transitions Interaction of peptide with the cubic phase, self diffusion, in vitro and in vivo release, enzymatic degradation in simulated intestinal fluid

Polarized light microscopy, smallangle X-ray scattering (SAXS), differential scanning calorimetry (DSC) Static X-ray diffraction, timeresolved X-ray diffraction Polarized light microscopy, nuclear magnetic resonance (NMR)

Effect of lidocaine on the phase behavior

Polarized light microscopy, SAXS

Glycerol monooleate/sesame oil/metronidazole benzoate – suspension upon contact with gingival fluid transforms into reversed hexagonal phase (periodontal) Glycerol monooleate/water(35% w/w)/vitamin E TPGS, hydroxychloroquine sulfate, diclofenac sodium, aspirin Glycerol monooleate/glycerin/AG337 (antitumorogenic substance); oral administration Glycerol monooleate/water/cytochrome c

Phase diagram, in vitro drug release

DSC, viscosimetry, SAXS, polarized light microscopy

(Engström and Engström, 1992) (Norling et al., 1992)

In vitro drug release

/

(Wyatt, 1992)

In vitro drug release

DSC

Interaction between cytochrome c and glycerol monooleate cubic phase Phase diagram

SAXS, Fourier transform infrared spectroscopy (FTIR), DSC, electrochemical studies DSC, SAXS, Raman scattering

(Longer et al., 1996) (Razumas et al., 1996a)

Temperature–composition phase diagram

SAXS

Glycerol monooleate/water/glucose oxidase, ceruloplasmin Glycerol monooleate/water/chlorpheniramine maleate, pseudoephedrine HCl, propranolol HCl

Evaluation of glycerol monooleate as biosensor, diffusion coefficient Swelling kinetics, in vitro drug release

Holographic laser interferometry, NMR, chronoamperometry Polarized light microscopy, DSC

Glycerol monooleate/water/chlorpheniramin maleate, diltiazem HCl, propranolol HCl, pseudoephedrin HCl, phenylpropanolamine HCl, theophylline anhydrous Glycerol monooleate/water/chlorpheniramin maleate, guaifanesin, propranolol HCl (oral)

In vitro drug release, surface tension measurements, Polarized light microscopy absorption of drug to the glycerol monooleate

3

4

5

6

7 8

9

10 11 12

13

Glycerol monooleate/water introducing distearoylphosphatidylglycerol and lysozyme (5%, 7%, 8% w/w) Glycerol monooleate/water

21

Polarized light microscopy Effect of dissolution media and additives in the monoolein phases on the water uptake, in vitro drug release Glycerol monooleate/water/propantheline bromide, Phase diagram, swelling, in vitro drug release Polarized light microscopy oxybutynin HCl (vaginal application) Salbutamol sulphate, nicotine (transdermal Passive and electrically assisted transport / delivery) Polarized light microscopy Glycerol monooleate/water/chlorpheniramine Transformation from the lower viscosity phases maleate, propranolol HCl (parenteral application) (lamellar or isotropic solution) to cubic–phase diagram, in vitro drug release In vitro mucoadhesive properties, influence of drug Mucoadhesion: “flushing” Glycerol monooleate and monolinolein/water/ miconazole isosorbide mononitrate, indometacin, on mucoadhesion bioadhesion test system and prochlorperazine tensiometric method; polarized light microscopy Glycerol monooleate/water/cefazolin, cefuroxim Stability (against hydrolysis and oxidation), assay / and degradation products at 22  C, 37  C and 50  C Glycerol monooleate/water/insulin Integrity of the secondary structure, physical Circular dichroism (CD) stability, optical density, aggregation profile Glycerol monooleate/water/insulin In vitro release, biological activity of insulin (rat) Polarized light microscopy

22

Glycerol monooleate/water/ubiquinone-10

23

Lipid–water phases

24

Glycerol monooleate/water liquid crystal systems with 15%, 20%, 30%, 35% w/w water Glycerol monooleate/water liquid crystal systems with 10%, 22%, 30% w/w water Glycerol monooleate and polymerizable 1,2diacylglycerol Glycerol monooleate/water

14

15 16 17

18

19 20

25 26 27

Electrochemical investigations

SAXS, FTIR, cyclic voltammetry technique Crystallographic study of cubic lipid systems Freeze-fracture electron microscopy, quantitative image processing Hot stage polarizing microscopy, Phase behavior, dielectric behavior dielectric spectroscopy Hot stage polarizing microscopy, Phase behavior, dielectric behavior dielectric spectroscopy Phase investigation – structure, diffusion coefficient Polarized light microscopy, NMR, SAXS Polarized light microscopy, SAXS Phase behavior with polar solvents: propylene glycol, dimethylsulfoxide, polyethylene glycol, ethanol

(Caffrey, 1987) (Ericsson et al., 1991)

(Razumas et al., 1996b) (Briggs et al., 1996) (Nylander et al., 1996) (Chang and Bodmeier, 1997c) (Chang and Bodmeier, 1997b) (Chang and Bodmeier, 1997a) (Geraghty et al., 1996) (Carr et al., 1997) (Chang and Bodmeier, 1998) (Nielsen et al., 1998)

(Sadhale and Shah, 1998) (Sadhale and Shah, 1999b) (Sadhale and Shah, 1999a) (Razumas et al., 1998) (Delacroix, 1998) (He and Craig, 1998b) (He and Craig, 1998a) (Srisiri et al., 1998) (Engström et al., 1998)

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7

Table 1 (Continued) No. System investigated

Parameters studied

Characterization Techniques/analyses

Refs.

28

Glycerol monooleate/water/lidocain HCl

Max. loading, drug compatibility in the sponge phase, diffusion coefficient, in vitro drug release

/

29

Glycerol monooleate/water/ubiquinone-10

SAXS, polarized light microscopy

30

Glycerol monooleate/nicotine

31

Glycerol monooleate/water/clomethiazole, lidocaine, prilocaine, 4-phenylbutylamine Glycerol monooleate/water/[D-Ala2, D-leu5] enkephalin (buccal-adhesive peptide delivery system) Glycerol monooleate/water with oleic acid, propylene glycol, phospholipids or surfactants/ tramadol HCl (subcutaneous, intramuscular or intrathecal injections) Glycerol monooleate/diglycerol monooleate/water

Solubilization of ubiquinone-10 in the glycerol monooleate/water system (86% glycerol monooleate) Effect of glycerol monooleate as bioadhesive substance in the suppositories release/flux/rectal delivery, in vitro drug release, caco-2 cell permeability studies Drug partition into the lipid bilayers

(Alfons and Engstrom, 1998) (Barauskas et al., 1999)

32

33

34 35

36 37

38 39

40 41

42

43

44 45 46 47 48

49

50

51 52

53

54

DSC, SAXS, MTT toxicity assay

(Dash et al., 1999)

SAXS

(Engström et al., 1999) (Lee and Kellaway, 2000) (Malonne et al., 2000)

Swelling of matrices, in vitro drug release

Polarized light microscopy

In vitro drug release, in vivo drug release (rat)

/

Microstructure

13

C NMR, polarized light microscopy, (Pitzalis et al., SAXS, rheology 2000) Glycerol monooleate/water/tricosane Curvature elastic properties of glycerol monooleate SAXS, volume measurements by DMA (Vacklin et al., in water (bending elasticity), structural and 2000) energetic analysis Glycerol monooleate/water Structure, stability and transformation of the Pn3m Synchrotron X-ray diffraction (Pisani et al., phase under pressure 2001) Influence of drug of different polarity on phase Glycerol monooleate/water/sodium decanoat, (Caboi et al., SAXS, NMR, polarized light decanoic acid, dodecanoic acid, acetyl salicylic acid, behavior, stability microscopy 2001) retinol, 1-adamantanamine Fluorine labeled poly(amidoamine) dendrimer, (Jeong et al., Diffusion of globular macromolecule-synthesized NMR synthesized by Michael reaction water-soluble dendrimer in cubic phase 2002) Synchrotron SAXS Glycerol monooleate/maleimide(triethylene glycol) Mechanism of formation under physiological (Angelova ether lipid/water system loaded by immunoglobulin hydration conditions (excess water and appropriate et al., 2003) Fab fragments, whole IgG, albumin, human salt concentration and pH) and structural transferrin, fibrinogen parameters Glycerol monooleate/n-octyl-b-D-glucopyranoside/ Thermal behavior SAXS (Persson et al., water 2003) Glycerol monooleate/water/pro drug 5Fluorescence spectroscopy (Turchiello Photodynamic activity, stability aminolevulonic acid, its ester derivatives, chlorine et al., 2003) compounds (m-THPC) (topical application in photodynamic therapy) Topology of the mesophase, phase behavior of the SAXS, FTIR Incorporation of cytochrome c into glycerol (Lendermann monooleate cubic mesophases dependent on lipid system, the lipid conformational states, and Winter, concentration, temperature and pressure hydration properties 2003) Concentrated emulsions and cubic phases based on In vitro drug release, partition coefficient, phase (Fa et al., SAXS, rheology, interfacial tension fluorinated and hydrogenated oils and surfactants diagram, interfacial tension measurements 2004) with caffeine Glycerol monooleate, sponge phase with 2-methyl- Influence of detergents, drugs, lipids on the sponge Polarized light microscopy (Ridell et al., 2,4-pentanediol phase 2003) Lauric acid, monolaurin, simulated endogenous SAXS, polarized light microscopy (Kossena In vitro drug release, absorption in rat model intestinal fluid et al., 2004) Floating gastroretentive system loaded by (Kumar et al., Effect of PEG 4000, PEG 10000 and stearic acid on Gamma scintigraphy chlorpheniramine maleate, diazepam floatability, in vitro drug release 2004) H2O2/glycerol monooleate (topical disinfected gel DSC, polarized light microscopy, SAXS (Kim et al., In vitro release, adhesiveness of cubic phase for a wounded skin) 2004) Influence of cyclosporine A on the phase structure Rheology, dielectric spectroscopy Glycerol monooleate/water liquid crystal systems (Bonacucina with 10%, 22%, 30% w/w water, incorporated et al., 2005) cyclosporine A (1% w/w) Floated system loaded by acid-labile enzyme – Water uptake, in vitro drug release, proteolytic Polarized light microscopy, gamma (Shah and serratiopeptidase activity scintigraphy Paradkar, 2005) (Mezzenga Glycerol monooleate/water and different Phase diagram, morphology, topology of liquid Polarized light microscopy, SAXS, et al., 2005) hydrophilic mono-, oligo-, and polysaccharides crystalline structures oscillatory shear rheometry, shear rheology, molecular dynamics simulations Glycerol monooleate/water (30%)/iopamidol Viscoelastic properties/structure Rheology, SAXS (Shui et al., 2005) Synchrotron X-ray small-angle Glycerol monooleate/water (20% w/w)/cytochrome Phase behavior as a function of temperature, (Kraineva c (0.2–10% w/w) pressure and protein conc., kinetics of various lipid diffraction, time-resolved SAXS et al., 2005) mesophase transformations Polarized light microscopy Glycerol monooleate/water/salicylic acid Influence of drug on the liquid crystalline phase, (Lara et al., effects of swelling and drug loading on the release 2005) mechanism; structure morphology, swelling kinetics, in vitro drug release Glycerol monooleate and tryptophan/lysozyme/ SAXS, CD, electrophoresis (Clogston and In vitro release, partition coefficient ovalbumin, apo-ferritin, cytochrome c, DNA Caffrey, 2005)

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Table 1 (Continued) No. System investigated

Parameters studied

Characterization Techniques/analyses

Refs.

55

In vitro permeation studies

/

Photodynamic activity

Polarized light microscopy, fluorescence spectroscopy

(Lopes et al., 2005) (Bender et al., 2005)

56

57 58 59

60

61

62 63

64

65

66

67 68 69

70 71

72

73 74 75

76

433 434 435 436 437 438 439 440 441 442 443 444 445 446

Glycerol monooleate used as penetration enhancer for the topical delivery of cyclosporine A Cubic phase (glycerol monooleate and phytantriol) incorporated d-aminoluvulinic acid and its methyl ester, topical administration Glycerol monooleate/water

Transformation from cubic gyroid to cubic diamond phase Glycerol monooleate (63% w/w)/aqueous solution Hydration dynamics of confined water in aqueous containing 4 mM tryptophan–alkyl ester (37% w/w) nanochannels Glycerol monooleate/limonene oil/water ternary Structure and viscoelastic properties of the Fd3m system phase

(Rappolt, 2006) Femtosecond-resolved fluorescence (Kim et al., dynamics 2006) (Pouzot et al., Polarized light microscopy, SAXS, shear rheology, turbidimetry, density 2007) measurements Biocathodes and bioanodes for electrochemical (Nazaruk and Applicability of the matrix for holding enzymes: / sensing and biofuel cells glucose oxidase, pyranose oxidase, lactase Bilewicz, 2007) SAXS Glycerol monooleate/water/anionic and cationic Effect of anionic and cationic peptides on the (Yaghmur peptides stability of Pn3m phase of the glycerol monooleate/ et al., 2007) water system Glycerol monooleate/oleyl glyceride/0.1 M HCl and In vitro drug release, oral bioavailability in rats Polarized light microscopy (Boyd et al., cinnarizine 2007) Phase diagram, in vitro skin penetration and Vit. K in: glycerol monooleate hexagonal phase, (Lopes et al., / liquid vaseline, glycerol monooleate nanodispersion transdermal delivery 2007) of hexagonal phase Surface tension measurement, in vitro drug release Polarized light microscopy, DSC Sodium salicylate in cubic phase: glycerol (Choi et al., monooleate and hydrophobic polymer poly(N2007) isopropylacrylamide) Moisture content, in vitro drug release, stability Gentamicin sulphate/glycerol monooleate/water Spectrophotometry, GC, rheology, hot (Ouedraogo et al., 2008) cubic phase, bioresorbable bone implant for chronic stage microscopy, TGA, DSC, osteomyelitis determination of moisture content (Karl Fischer), SAXS Biocompatibility and preliminary toxicity in mice Gentamicin sulphate/glycerol monooleate/water Mira Plus analyses (clinical chemistry (Henschel cubic phase, bioresorbable bone implant for chronic assays) et al., 2008) osteomyelitis Preconcentrate: metronidazole benzoate/ Water absorption mechanism (Enslin method), in Polarized light microscopy, rheology (Fehér et al., Cremophor EL(or RH40)/Miglyol vitro drug release 2008) Cyclosporine A in glycerol monooleate/tricaprylin/ Effect of 3 dermal penetration enhancers: Polarized light microscopy, SAXS, (Libster et al., water phosphatidylcholine, ethanol, Labrasol DSC, rheology 2007) Vit. E, glucose, Allura Red and FITC-dextran in cubic Diffusion coefficient, in vitro release, in vivo oral (Lee et al., Polarized light microscopy, SAXS and hexagonal phase prepared from glycerol absorption in rat 2009) monooleate and phytantriol Vit. E acetate, glucose in glycerol monooleate and (Fong et al., Respond to different temperature, in vitro release Polarized light microscopy, SAXS phytantriol cubic and hexagonal phase study, in vivo subcutaneous absorption study 2009) In vitro drug release, viscosity, bioburden, sterility Polarized light microscopy, Low viscosity precursor for cubic phase: (Ahmed et al., oligonucleotides in glycerol monooleate/water/ sterilization methods 2010) cosolvent Radio-labelled glucose in glycerol monooleate cubic, In vitro drug release SAXS (Phan et al., hexagonal, micellar cubic crystalline phases and 2011) inverse micelle Bupivacaine/glycerol monooleate/medium chain Diffusion coefficient, effect of varying the lipid (Yaghmur SAXS, HPLC triglycerides composition on nanostructure, in vitro drug release et al., 2012b) Clonidine/glycerol monooleate/hyaluronic acid for Rheology, DSC, TGA, polarized light (Réeff et al., Syringeability, in vitro drug release parenteral administration (intraarticular) microscopy 2013a) Influence of sodium oleate and soybean oil in Rheology Clonidine/glycerol monooleate/hyaluronic acid/ (Réeff et al., sodium oleate (or soybean oil) for parenteral formulation on the release properties (in vitro drug 2013b) administration (intraarticular) release), syringeability d-Aminolevulinic acid or methylaminolevulinate in In vivo study in mice Polarized light microscopy, SAXS, (Evenbratt 1-glyceryl monooleyl ether/aprotic solvent/water fluorescence spectrophotometry et al., 2013)

35%). All drugs (highly water soluble drugs of smaller molecular weight such as hydroxychloroquine sulfate, diclofenac sodium, and large molecules such as vitamin E TPGS) showed sustained release properties after incorporation into the cubic phase and were compared with their solution. A small increase of the dissolution rate of hydroxychloroquine sulfate (chosen as example for a small molecule) was found and indicates that the size of the molecule influences the release rate. The feasibility study of using the cubic liquid crystalline phases made of glycerol monooleate as a matrix for controlled release of an antitumorogenic substance, AG337, was done by Longer et al. (1996). There was an initial release at the beginning (40% released in the first 15 min. during the initial contact between the formulation and an acidic release medium) until a condition has

SAXS

been reached where the glycerol monooleate intrinsically controls the AG337 release through phase transitions (these are dependent upon the dynamics of water uptake, 73% released in 24 h). The effect of the lipid composition on the long-term stability of the enzymes, glucose oxidase and ceruloplasmin, entrapped in the glycerol monooleate/water cubic liquid crystalline phase was investigated by Nylander et al. (1996). The lipid mixture, glycerol monooleate and phosphatidylcholine, 4:1 w/w, stabilizes the glucose oxidase incorporated (30% of its activity after 80 days for this mixture compared to only some rest activities after 20 days for glycerol monooleate alone). Furthermore, they showed that dimensions of the water channels in the bicontinuous cubic phases are in the same range as the size of a typical globular protein. The entrapment of protein itself depends on the interactions with the

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447 448 449 450 451 452 453 454 455 456 457 458 459 460

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lipid bilayer and the physical dimensions of the space, i.e., the water channels available for protein. The important factors for the guest molecules release are the degree of swelling, the curvature of the interfaces and the type of cubic liquid crystalline phases. In addition the group of Bodmeier demonstrated the sustained release of chlorpheniramine maleate and pseudoephedrine hydrochloride from glycerol monooleate/water systems (Chang and Bodmeier, 1997b,c, 1998). The drug release follows the squareroot of time relationship during the first 12 h, indicating a diffusion-controlled drug release mechanism. Within 24 h, pseudoephedrine hydrochloride was completely released, however, some other water soluble drugs (chlorpheniramin maleate, diltiazem HCl, propranolol HCl, phenylpropanolamine HCl, theophylline anhydrous) showed an incomplete release from the cubic phase. Similarly, Wyatt (1992), also investigated the release properties of hydrophilic drugs incorporated into the glycerol monooleate matrix, and again, an incomplete release was obtained for drugs such as vitamin E, TPGS or aspirin. Considering the drug absorption to the monoglycerides, and surface tension, Chang and Bodmeier (1997b,c, 1998), concluded that an incomplete release of hydrophilic drugs from the glycerol monooleate systems was due to the binding of the drug molecules to the glycerol monooleate liquid crystalline phases. However, later in 2001, it was suggested that the binding of drug molecules to the glycerol monooleate liquid crystalline phases is incorrectly referred instead of a bilayer participation (Shah et al., 2001). Hence, the drug incorporated into bilayers is a more appropriate explanation for the above mentioned incomplete drug release phenomenon. This was attributed mainly to the specific drug interaction with surfactant components which generally could also be used for fine tuning of the release profiles (Drummond and Fong, 1999). Investigating the drug release from glycerol monooleate matrices containing the same amount of drug but different amount of water (10–30%), Chang and Bodmeier (1997c), showed an increased drug release with increasing water content (10–30%). Under these conditions the hydrophilic domain also increased, and the drug release increased despite the rise in matrix viscosity. These differences occurred only within the initial dissolution phase, while for longer time periods nearly parallel drug release curves were obtained. This is due to the cubic phase created during the release later, irrespective of the initial water content. As the main parameters which are able to control the drug release from glycerol monooleate matrices, Chang and Bodmeier (1997c), emphasized: the surface-to-volume ratio, the drug loading and the water content of the lipid matrix. Furthermore, the group of Bodmeier also demonstrated that there were no drug release differences between glycerol monooleate matrices prepared from different sources (Myverol 18-99 produced by Eastman Chemical Co., Kingsport, TN, GMOrphic-80 produced by Eastman Chemical Co., Kingsport, TN and Dimodan DGMO produced by Grindsted Products, Brabrand, Denmark). The release of the drug from glycerol monooleate bases is governed primarily by the type of swollen phase and the main component of the monoglyceride (also affecting the melting point) (Chang and Bodmeier, 1997c). The addition of drugs into the glycerol monooleate matrices affected their phase and release behavior (Engström, 1990; Engström and Engström, 1992). It was shown that above a certain concentration, hydrophilic drugs (chloropheniramin maleate, propranolol HCl) transformed the cubic phase into a lamellar phase, whereas lipophilic drugs (ibuprofen, propranolol) transformed the cubic phase into a reversed hexagonal phase (Chang and Bodmeier, 1997b). Developing a potential vaginal delivery system based on glycerol monooleate/water liquid crystalline phases, Geraghty et al. (1996), incorporated two amphiphilic drugs: propantheline bromide and oxybutynin HCl in this system, and proposed their

9

partition mostly at the lipid–water interface. Both drugs investigated promoted the formation of the lamellar phase and showed the sustained release over a period of 18 and 20 h. Geraghty et al. (1996), concluded that the drug release profiles depend upon the solubility of the drug in the lipid base and the extent of partitioning into the lipid bilayer. Furthermore, also the release and swelling behavior of glycerol monooleate-based drug delivery systems were studied by Chang and Bodmeier (1997a). The drug release and swelling behavior depended on the composition and purity of the lipid matrix and the components of the gastrointestinal tract. In the same study it was shown that the water uptake of a glycerol monooleate based system is rapid and levelled off after 4 h (at both pH investigated 1.2 and 7.4). Thus, the pH of the medium will not affect the type of the swollen liquid crystalline phase. The glycerol monooleate cubic phase is too viscous to be injected directly, either intramuscularly or subcutaneously. Consequently, Chang and Bodmeier (1998), developed a low viscosity glycerol monooleate parenteral delivery systems by addition of a third component, the drug itself, or by the addition of organic solvents. Chlorpheniramine maleate and propranolol HCl showed that upon increasing the drug content, the cubic phase was transformed into the lamellar phase. Furthermore, chlorpheniramine maleate showed that by further increasing the drug content, a transformation into an isotropic phase was observed. However, this seems to be not a general law, i.e., propranolol hydrochloride did not show an isotropic solution phase with such further increasing drug content (Chang and Bodmeier, 1998). The mucoadhesive properties of glyceryl monooleate and glyceryl monolinoleate were investigated in vitro by “flushing” bioadhesive test and a tensiometric method (Texture Analyzer) by (Nielsen et al., 1998). Tensiometric measurements showed that the unswollen monoglycerides have the largest mucoadhesion, followed by the partly swollen lamellar phase and the fully swollen cubic liquid crystalline phase. The values for the work of adhesion were in the range 0.007–0.048 mJ cm2. Probably the mechanism of mucoadhesion is unspecific and involves dehydration of the mucosa. Incorporating cefazolin in the glycerol monooleate cubic phase, Sadhale and Shah (1998), presented that cefazolin was six-fold more stable in the cubic phase than in solution. For cefazolin 50 mg/g incorporated in the cubic phase, the energy of activation was found to be 23.4 kcal/mol, whereas in solution, the energy of activation was 4.2 kcal/mol. Similarly, they showed that cefuroxim incorporated in cubic phase degraded significantly slower at 22  C ( kd = 0.0013  0.00003 h1) than in solution conc. 200 mg/g (kd = 0.0029  0.00003 h1), resulting a 2.2-fold slower degradation. Thus, it was demonstrated that the cubic phase is able to be used as stabilizer against hydrolysis and oxidation at RT (22  C) and at 37  C. The enhanced stability was connected with the lower mobility and reactivity of uniquely structured water in the cubic liquid crystalline phase (Sadhale and Shah, 1998). Furthermore, the same authors investigated the glycerol monooleate self-assembly structure to prevent insulin from aggregating (Sadhale and Shah, 1999a,b) In this study it was demonstrated that the cubic phase is able to protect insulin from agitation induced aggregation successfully with little effect on its biological activity (Sadhale and Shah, 1999a). A further investigation used ubiquinone-10 which was entrapped in the reversed bicontinuous cubic phase of aqueous glycerol monooleate and the cyclic voltammetry technique was used to investigate the redox activity of the ubiquinone-10 in such a system (38.7% of water, 0.5% of ubiquinone w/w) (Barauskas et al., 1999; Razumas et al., 1998). Using the electrochemical method, the diffusion coefficient of ubiquinone-10 in such a system was determined to be 1.9  108 cm2/s. Ubiquinone-10 (in concentration

Please cite this article in press as: Milak, S., Zimmer, A., Glycerol monooleate liquid crystalline phases used in drug delivery systems. Int J Pharmaceut (2014), http://dx.doi.org/10.1016/j.ijpharm.2014.11.072

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lower than 0.5% w/w) has no effect on the glycerol monooleate bilayer thickness and swelling behavior of phases, but it promotes thermotropic transition into the reversed hexagonal phase at a lower concentration. This is due to the ubiquinone-10 partitioning into the reversed hexagonal region where the glycerol monooleate chains probably should be stressed upon the phase transition. At the concentration of ubiquinone-10 above 0.5% w/w, inside the initially homogenous phases a solid ubiquinone-10 phase appeared which could be due to ubiquinone-10 lateral diffusion in the glycerol monooleate bilayer (Barauskas et al., 1999). Glycerol monooleate was also investigated as bioadhesiveness in the design of rectal delivery systems of nicotine (Dash et al., 1999). Using a Caco-2 cell permeation test it was shown that the nicotine flux in the formulation with glycerol monooleate is lower in comparison to a nicotine solution. In this study this observation was explained by an additional diffusion barrier created by the adhesion of glycerol monooleate to the cell monolayer (Dash et al., 1999). A pH-dependent partitioning of a drug into a lipid bilayer in a cubic liquid crystalline phase was demonstrated by Engström et al. (1999). The equilibration time for such an experiment is controlled by experimental conditions such as agitation, temperature and interfacial area between the cubic phase and the aqueous bulk. A shorter equilibration time is obtained by enhancing drug diffusion by heating, by increasing the interface between the cubic phase, and the aqueous bulk, as well as by decreasing the amount of the cubic phase (Engström et al., 1999). Malonne et al. (2000), showed that glycerol monooleate–water and quaternary (oleic acid–phospholipid–glycerol monooleate– water) formulations have controlled drug release profiles which were accelerated by surfactant adjunction. Pluronic1 F68 accelerated the release in glycerol monooleate/water formulations. Partial substitution of lipid with oleic acid showed a slower drug release, but while increasing the concentration of oleic acid again a similar release profile of the glycerol monooleate/ water system was observed. These changes are connected with the structural changes in the arrangement of the lipids (Malonne et al., 2000). Further studies investigated the diffusion of large hydrophilic molecules. As one example a fluorine labelled poly(amidoamine) dendrimer was encapsulated into the cubic phase (Ia3d symmetry) and its diffusion in the water channels was investigated by NMR (Jeong et al., 2002). The hydrodynamic diameter of the fluorinated dendrimer was determined with 32.6 Å and the diffusion coefficient in the water channels of the cubic phase was found to be 1 1012 m2/s at 25  C, which was compared to the free diffusion coefficient of the dendrimer in water with 1.42  1010 m2/s. From this value it was estimated that small globular proteins or molecules similar to the above mentioned dendrimer can diffuse sufficiently enough within the stabilized cubic phase to achieve modified release properties (Jeong et al., 2002). More detailed in terms of the partition of large hydrophilic molecules Angelova et al. (2003), encapsulated proteins (immunoglobulin Fab fragments, whole IgG, albumin, transferrin, fibrinogen) in the glycerol monooleate matrix and investigated their structure under physiological conditions (excess water, appropriate salt concentration and pH) by SAXS. Glycerol monooleate was the main component of such a system and it was mixed with a second uncharged amphiphilic component, a maleimide(triethylene glycol) ether lipid comprising a polar terminal group which is reactive to free SH groups. Despite of many authors who previously assumed that water-soluble proteins are mainly located in the water channels of the bicontinuous cubic lattices, in this study, Angelova et al. (2003), assumed that the proteins are most likely located at the interface or associated to the surface of the interconnected cubosomal entities, due to their

surface activity and intermolecular interactions. Further, it was shown that the blood proteins do not destabilize the structural organization of the bicontinuous cubic media prepared with glycerol monooleate and maleimide(triethyleneglycol) ether at RT and higher temperature as well, as they marginally influence the structural parameters. A potentially new application of glycerol monooleate/water system was investigated by Turchiello et al. (2003), to deliver prodrugs and photosensitizers such as 5-aminolevulinic acid for topical applications in photodynamic therapy. The gel formulation prepared (glycerol monooleate/water, 70/30, w/w) was able to maintain the stability and photodynamic activity of the incorporated molecules. Further structural changes of the cubic system was reported by Persson et al. (2003). This study demonstrated that the cubic liquid crystalline phases are stable with small fractions of n-octylb-D-glycopiranoside, while higher n-octyl-b-D-glycopiranoside concentrations trigger a cubic-to-lamellar phase transitions. Interestingly, both the Ia3d and Pn3m cubic structures could be in equilibrium with excess water in this ternary system (Persson et al., 2003). Kraineva et al. (2005), and Lendermann and Winter (2003), demonstrated that the incorporation of cytochrome c into the glycerol monooleate cubic phase has significant effects on the structure and pressure stability of this system. At low concentration of cytochrome c (

Glycerol monooleate liquid crystalline phases used in drug delivery systems.

During the last few decades, both scientific and applied research communities have shown increased attention to self-assembled lyotropic liquid crysta...
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